Diphenylmethane derivatives as SGLT2 inhibitors

Patent metadata

Field	Value
Publication number	US-9371303-B2
Application number	US-201514593071-A
Country	US
Kind code	B2
Filing date	Jan 9, 2015
Priority date	Jun 1, 2011
Publication date	Jun 21, 2016
Grant date	Jun 21, 2016

Abstract

A compound with a diphenylmethane moiety having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney is disclosed. A pharmaceutical composition including the compound as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly diabetes is disclosed. A method for preparing the compound, and a method for preventing or treating metabolic disorders, particularly diabetes, by using the compound is provided.

First claim

What is claimed is:

1. A compound of formula I, or a pharmaceutically acceptable salt or a thereof:

wherein,
X is oxygen or sulfur;
Y is C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, C 1-7 alkylsulfinyl, C 1-7 alkylsulfonyl, or C 1-7 alkylthio;
ring A is

said R 1a , R 1b , R 4a , R 4b and W being each independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, C 2-7 alkenyl-C 1-7 alkyloxy, C 2-7 alkynyl-C 1-7 alkyloxy, C 3-10 cycloalkyl, C 5-10 cycloalkenyl, C 3-10 cycloalkyloxy, phenyl-C 1-7 alkoxy, mono- or di-C 1-7 alkylamino, C 1-7 alkanoyl, C 1-7 alkanoylamino, C 1-7 alkoxycarbonyl, carbamoyl, mono- or di-C 1-7 alkylcarbamoyl, C 1-7 alkylsulfonylamino, phenylsulfonylamino, C 1-7 alkylsulfanyl, C 1-7 alkylsulfinyl, C 1-7 alkylsulfonyl, C 6-14 arylsulfanyl, C 6-14 arylsulfonyl, C 6-14 aryl, 5 to 13-membered heteroaryl, or 5 to 10-membered heterocycloalkyl,
said R 2 being each independently hydroxy, C 1-7 alkyl, or C 1-7 alkoxy,
said n being an integer of 0 to 3,
said Z 1 , Z 2 , and Z 3 being each independently —CH 2 —, —CH═, —(CO)—, and
said p being an integer of 1 to 3;
ring B is

with the proviso that when ring A is A-1, then ring B is B-2,
wherein,
said R 5a , R 5b , R 6a , and R 6b being each independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, cyano, nitro, amino, carboxy, oxo, C 1-7 alkyl, C 1-7 alkylthio, C 2-7 alkenyl, C 2-7 alkynyl, C 1-7 alkoxy, C 1-7 alkoxy-C 1-7 alkyl, C 2-7 alkenyl-C 1-7 alkyloxy, C 2-7 alkynyl-C 1-7 alkyloxy, C 3-10 cycloalkyl, C 3-7 cycloalkylthio, C 5-10 cycloalkenyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkyloxy-C 1-7 alkoxy, phenyl-C 1-7 alkyl, C 1-7 alkylthio-phenyl, phenyl-C 1-7 alkoxy, mono- or di-C 1-7 alkylamino, mono- or di-C 1-7 alkylamino-C 1-7 alkyl, C 1-7 alkanoyl, C 1-7 alkanoylamino, C 1-7 alkylcarbonyl, alkoxycarbonyl, carbamoyl, mono- or di-C 1-7 alkylcarbamoyl, C 1-7 alkylsulfonylamino, phenylsulfonylamino, C 1-7 alkylsulfinyl, C 6-14 arylsulfanyl, C 6-14 arylsulfonyl, C 6-14 aryl, 5 to 13-membered heteroaryl, 5 to 10-membered heterocycloalkyl, 5 to 10-membered heterocycloalkyl-C 1-7 alkyl, or 5 to 10-membered heterocycloalkyl-C 1-7 alkoxy, and
said ring C being C 3-10 cycloalkyl, C 5-10 cycloalkenyl, C 6-14 aryl, 5 to 13-membered heteroaryl, or 5 to 10-membered heterocycloalkyl;
said alkyl, alkenyl, alkynyl, or alkoxy is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-7 alkyl, and C 2-7 alkynyl; and
said cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C 1-4 alkyl, and C 1-4 alkoxy.

2. The compound of claim 1 , wherein said ring A-2 is selected from the group consisting of:

3. The compound of claim 1 , wherein said ring B-1 is selected from the group consisting of:

in which R 7 is hydrogen, or C 1-7 alkyl, and
R 8a and R 8b are each independently C 1-7 alkyl, or R 8a and R 8b are connected to form a 5 to 10-membered heterocycloalkyl.

4. The compound of claim 1 , wherein said ring B-2 is selected from the group consisting of:

5. The compound of claim 1 , wherein said ring A is a benzene, indane, indene, , , , tetrahydronaphthalene, dihydronaphthalene ring, , , , which is optionally substituted with a substituent as defined in claim 1 .

6. The compound of claim 1 , wherein said ring B is a quinoline, quinoxaline, 3,4-dihydro-2H-benzo[b][1,4]dioxepine, 2,3-dihydrobenzo[b]thiophene, indazole, indole, 2,3-dihydrobenzo[b][1,4]dioxine, benzodioxole, indane, tetrahydronaphthalene, 3,4-dihydro-2H-thiochromene, dihydrobenzofuran, benzo[d][1,3]oxathiole, tetrahydroquinoline, or 3,4-dihydro-2H-benzo[b][1,4]oxazine ring, which is optionally substituted with a substituent as defined in claim 1 .

7. The compound of claim 1 , which is selected from the group consisting of:
(2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-ethoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-bromo-6-(4-ethylbenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-fluoro-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2R,3S,4R,5R,6S)-2-(hydroxymethyl)-6-(6-(4-methoxybenzyl)-7-methyl-2,3-dihydro-1H-inden-4-yl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-chloro-6-(4-ethoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
(2S,3R,4R,5S,6R)-2-(6-(4-ethoxybenzyl)-7-methyl-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(5-(4-(ethoxybenzyl)-6-methylbiphenyl-3-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(5-((2,3-dihydrobenzo [b][ 1,4]dioxin-6-yl)methyl)-6-methylbiphenyl-3-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-methyl-5-(thiophen-3-yl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-methyl-5-(thiophen-2-yl)phenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6S)-2-(7-bromo-6-(4-methoxybenzyl)-2,3-dihydro-1H-inden-4-yl)-6-methoxy-tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-chloro-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-7-methyl-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(7-(difluoromethyl)-6-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydro-1H-inden-4-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(2-(allyloxy)-4-chloro-5-(4-methoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(4-chloro-5-(4-ethoxybenzyl)-2-methoxyphenyl)-6-(methylsulfonyl)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(4-chloro-3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol;
(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)-5-methoxyphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

Assignees

• Green Cross Corp

Inventors

• Choi Soongyu
• Song Kwang-Seop
• Lee Suk Ho
• Kim Min Ju
• Seo Hee Jeong
• Park Eun-Jung
• Kong Younggyu
• Park So Ok
• Kang Hyunku
• Jung Myung Eun
• Lee Kinam
• Kim Hyun Jung
• Lee Jun Sung
• Lee Min Woo
• Kim Mi-Soon
• Hong Dong Ho
• Kang Misuk

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D407/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title